Renal failure is distinguished between acute renal failure or acute kidney injury and chronic renal failure. The basic difference between acute and chronic renal failure is the progression of the disease, which is fast for acute renal failure (usually within days or weeks) and slow for chronic renal failure (usually in the range of years). Both acute renal failure and chronic renal failure can result in a complete loss of renal function, causing the subject to depend on renal replacement therapy, such as hemodialysis or kidney transplantation. The incidence of renal failure has doubled since 1990, most likely caused by the increase of the incidence of diabetes and hypertension, the two major causes for kidney failure.
Chronic renal failure is an irreversible destruction of renal function and usually is associated with the decreased size of the kidneys. It does not cause pain, which is an important reason that it is often not diagnosed until late stages, reducing the success rate of therapy. Treatment usually is started when the kidneys are already largely and irreversibly destroyed. In contrast, acute renal failure can be reversible, depending on its cause and on the success of the therapy. The success of the therapy depends, to a large extent, on the early diagnosis.
Renal failure can be determined by calculating the glomerular filtration rate (GFR). The GFR describes the total volume of primary urine which is filtered by both kidneys within a distinct time interval. The GFR is normally >90 ml/min/body surface. It can be calculated by measuring either exogenic markers or endogenic markers.
Specifically, the GFR can be determined by injecting known amounts of exogenic diagnostic substances such as Inulin, radioactive substances (such as Chromium (Cr51-EDTA), Technetium (99mTC-DTPA), and Cobalt (Co57-vitamin B12)), or radiopaque material (such as Iohexol and Iothalamate), and subsequently measuring the excretion of these substances.
However, these tests are time-consuming, inconvenient, and expensive as they require collecting and measuring the blood and/or the urine excreted repeatedly over a specified time period. Other disadvantages are the use of potentially harmful materials, such as radioactive or radiopaque materials, and the use of expensive and difficult to measure substances, such as Inulin. Thus, calculating the GFR using exogenic substances is usually only used in scientific studies and not clinical practice.
Renal failure can also be determined using endogenic biomarkers, among which serum creatinine clearance is the most commonly used in clinical practice. Creatinine originates from muscle tissue and is increasingly secreted by renal tubules with decreasing renal function. Creatinine clearance can be used to diagnose chronic, as well as acute, renal failure.
Serum creatinine levels depend on age, sex, diet, muscle mass, ethnic background, physical activity, and disease. It is also secreted by the tubuli of the kidneys independent of kidney disease (Nephrol Dial Transplant, 2002, 17 (Suppl. 7):7-15) or can be secreted via the gut. All these factors impair the reliability of creatinine clearance for diagnosis of renal failure.
Various correction formulas are known to improve the accuracy of creatinine-based GFR determinations, by including additional metadata such as race, weight, body height, and body surface. However, these formulas may not work correctly under certain circumstances. For example, if the subjects are bodybuilders, vegetarians, obese, or suffer from diabetes, hypertension, or chronic liver disease. In addition, these formulas are not useful in determining the GFR of healthy subjects or of subjects suffering from only mild or moderate renal failure. Finally, the GFR may decline as much as 50% before serum creatinine starts to increase above reference levels. These limitations demonstrate that correction formulas often are not suitable for all stages of renal failure (from mild GFR reduction to renal failure).
Another endogenic biomarker for renal failure diagnosis is Cystatin C, a 120 amino acid, 20 kDa cysteine-protease inhibitor present in most body fluids. It is excreted by the kidneys. In contrast to creatinine, the expression of Cystatin C is relatively constant, independent of, e.g., muscle mass, body weight and age. Consequently Cystatin C is used as a biomarker of chronic renal failure. Some newer studies also indicate that it might also be useful as a diagnostic marker for acute renal failure (Kidney Int'l., 2004, 66:1115-1122). However, this has to be further investigated.
Cystatin C can be determined directly from blood samples. Therefore, there is no need for the time-consuming, inconvenient and error prone urine collection. Nevertheless, there are still limitations for timely and sensitive diagnosis of renal failure using Cystatin C. In addition, the suitability of Cystatin C for diagnosis of acute renal failure has not yet been validated.
NGAL is another promising endogeneous marker that appears to detect early stages of acute renal injury. NGAL has been shown to correlate with acute kidney injury in a variety of disease modalities and is detectable at an early stage of disease. The validity of NGAL for diagnosis of acute renal failure has yet to be fully determined.
Early detection and intervention is critical to effective treatment of effective treatment. However, the existing diagnosis methods have many disadvantages and limitations as described. Therefore, a need exists for novel methods for early diagnosis of renal failure.